Project Summary We propose to investigate the role and mechanisms of antiphospholipid antibodies (aPL) in the development of pathologically-proven ischemic brain infarction. Our primary objective is to determine whether aPL are an independent risk factor/predictor for ischemic brain infarction. A battery (portfolio) of aPL assays will be performed as there is currently controversy over which aPL assay or combination of aPL assays are best predictive of subsequent ischemic cerebrovascular disease. We will also analyze the role of aPL for various infarct locations and subtypes (small vessel, large vessel, thrombotic in the absence of atherosclerosis). We will also determine the significance of transient vs. persistent aPL positivity over time (a diagnostic laboratory criteria for the antiphospholipid antibody syndrome is persistence of aPL positivity) and the frequency and significance of the number of aPL positive assays (zero to 4). Additional objectives include confirming prior preliminary data on potentially important mechanisms by which aPL may play a role, specifically through altered annexin A5 resistance, anti-annexin antibodies, and aPL binding to domain I (the thrombogenic domain) of 2-glycoprotein I (2GPI). We propose a community-based study among older individuals who have agreed to donate their brains upon their death. Our study is well-powered to be able to detect an odds ratio (OR) of 2 or greater for the primary endpoint of pathologically-proven ischemic stroke. We have adequate power to compare multiple to single aPL positivity, and to assess mechanisms of aPL associated cerebrovascular disease at autopsy. The proposed study will take advantage of ante-mortem biologic specimens, clinical and post-mortem data from two ongoing large, longitudinal clinical-pathologic cohort studies: The Religious Orders Study (P30AG10161, R01AG15819) with more than 1,100 participants and about 425 brain autopsies to date, and the Rush Memory and Aging Project (R01AG17917) with more than 1,200 particpants and about 250 brain autopsies to date. This will be the first systematic study of a large, well-studied community-based cohort of older individuals for the risk conferred by aPL in pathologically-proven ischemic cerebrovascular disease. Also, for the first time, aPL other than aCL will be assayed in a well-studied prospective cohort of community- based subjects. Our study will also allow a direct comparison to other prospective cohort studies (without pathology) that found a single positive baseline aPL to be an independent risk factor for: (a) venous blood clots (deep venous thrombosis and pulmonary embolism) in men (Physicians Health Study) (Ginsburg et al 1992), (b) MI and stroke in men (Honolulu Heart Study) (Brey et al 2001), and (c) Stroke and TIA in women but not men (Framingham Cohort and Offspring Study)(Janardhan et al 2004).